Regulation of Smooth Muscle Myosin Light Chain Phosphatase by Multisite Phosphorylation of the Myosin Targeting Subunit, MYPT1

摘要

Background: Smooth muscle contraction is triggered primarily by activation ofCa2+/calmodulin-dependent myosin light chain kinase leading to phosphorylation of the regulatorylight chains of myosin II. Numerous contractile stimuli also induce inhibition of myosin light chainphosphatase thereby prolonging the contractile response. The phosphatase is a trimeric enzymecontaining a catalytic subunit, a regulatory, myosin-binding subunit (MYPT1) and a third subunit ofuncertain function. MYPT1 is phosphorylated at multiple sites by several kinases, which regulatephosphatase activity, protein-protein interactions and subcellular localization. The best-characterizedphosphorylation events involve phosphorylation by Rho-associated coiled-coil kinase (ROCK) atT697 and T855, which inhibits phosphatase activity, and phosphorylation by cAMP- or cGMPdependentprotein kinases (PKA and PKG, respectively) at S696, T697, S854 and T855, which hasno effect on phosphatase activity. Furthermore, phosphorylation by ROCK at T697 and T855 preventsphosphorylation by PKA or PKG at the neighboring serine residues. Some 30 phosphorylation siteshave been identified in MYPT1 with many more suggested by large-scale phosphoproteomicstudies. It is important to gain as complete understanding as possible of the complexphosphorylation-mediated mechanisms of regulation of MYPT1 functions in part because of theirinvolvement in pathological processes. For example, dysfunctional MYPT1 phosphorylation hasbeen implicated in the pathogenesis of several vascular disorders, including type 2 diabetes.Conclusion: Much effort is now being devoted to the development of novel therapeutics targetingMYPT1 and specific kinases involved in the phosphorylation of MYPT1.